IL-28 and IL-29 in Regulation of Antitumor Immune Response and Induction of Tumor Regression

Abstract

Type III interferons (IFNs), also known as IFN-λs, are recently described as a novel group of the cytokine family that shares with type I IFNs the same Jak/STAT intracellular signaling pathway driving the expression of a common set of IFN-stimulated genes despite the distinct receptor system usage from type I IFNs. Accordingly, type III IFNs exhibit multiple common biological features with type I IFNs including antiviral activity and antitumor activity in more restricted cell types. Early in vitro studies using human neuroendocrine and colorectal tumor cell lines displayed that, like type I IFNs, type III IFNs can exert direct biological effects on tumor cell growth and functions, such as an induction of apoptosis, by multiple mechanisms. Subsequently, an ensemble of studies based on the use of genetically modified murine tumor cells producing IFN-λ2 (IL-28A) or the in vivo delivery of naked plasmid DNA provided important information on the host-mediated antitumor mechanisms induced by locally produced IL-28A. Of note, these studies have revealed the immunomodulatory functions of type III IFNs, including biological effects on polymorphonuclear neutrophils, NK cells, and T cells, which mainly contribute to type III IFN-induced in vivo antitumor immunity. IFN-γ is partially involved in type III IFN-induced antitumor activity. Additionally, IL-12 enhances type III IFN-mediated antitumor action in the presence or absence of IFN-γ. On the whole, these findings provide clear evidence that type III IFNs have bioactivities to elicit antitumor immune response and indicate the possibility for the application of type III IFNs to cancer immunotherapy.